慢性髓细胞白血病慢性期患者接受酪氨酸激酶抑制剂治疗停药后的临床结局及其影响因素临床分析

Clinical analysis on outcomes in patients with chronic myeloid leukemia in chronic phase after tyrosine kinase inhibitors discontinuation and their influencing factors

摘要目的探讨慢性髓细胞白血病慢性期(CML-CP)患者接受酪氨酸激酶抑制剂(TKI)治疗停药后的临床结局及其影响因素。方法选择1999年1月至2018年4月于四川大学华西医院血液科接受常规门诊随访,停用TKI治疗时间超过6个月的16例CML-CP患者为研究对象。其中,男性患者为6例,女性为10例;诊断时中位年龄为39.5岁(24.8~53.8岁),TKI停药时中位年龄为45.5岁(30.3~69.0岁)。按照患者TKI停药后随访期内是否发生分子学复发,将其分为复发组(n=5)和未复发组(n=11)。采用回顾性分析方法收集患者TKI停药前、后的相关临床资料,分析其TKI停药的原因、TKI停药后无治疗缓解(TFR)情况及其可能的影响因素。本研究患者性别、CML分期、停药原因构成比等计数资料的组间比较,采用Fisher确切概率法;TKI治疗时间、开始接受TKI治疗至主要分子学反应(MMR)/深度分子学反应(DMR)的时间、MMR/DMR维持时间等,呈非正态分布计量资料的组间比较,采用Mann-Whitney U检验。采用Kaplan-Meier法计算患者TKI停药后6、12个月的TFR率。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。结果①本研究16例CML-CP患者中,因TKI相关不良反应、主动停药、妊娠/计划妊娠、经济困难、合并实体肿瘤原因,而停用TKI者分别为5、5、4、1和1例。16例CML-CP患者的停药前已接受TKI治疗的中位时间为53.0个月(34.0~156.0个月),其中15例患者于TKI停药前最佳疗效为获得DMR,1例仅获得MMR;患者TKI停药前持续获得DMR的中位时间为39.0个月(10.0~144.0个月)。②本研究16例CML-CP患者的停药后中位随访时间为17.0个月(7.0~75.0个月),截至随访终点,11例患者未发生分子学复发,TFR中位时间为12.0个月(2.0~75.0个月),患者TKI停药后6、12个月的TFR率分别为68.8%、61.9%。5例CML-CP患者发生分子学复发,中位复发时间为停药后4.0个月(2.0~5.0个月),复发时BCR-ABLIS水平为0.14%~0.88%。5例发生分子学复发患者中,4例患者分别于复发后第3、4、6、8个月重新开始接受TKI治疗,分别于重新接受TKI治疗的第2、3、4、5个月后获得MMR,第2、3、7、8个月获得分子学反应(MR)^4.5。③本研究5例CML-CP患者TKI停药后分子学复发均发生在停药后6个月内。复发组和未复发组CML-CP患者的性别、CML分期、停药原因、TKI治疗前接受α干扰素、TKI给药类型构成比,以及TKI治疗时间、开始接受TKI治疗至MMR/DMR时间、MMR/DMR维持时间、TKI停药年龄分别比较,差异均无统计学意义(P>0.05)。④ 16例CML-CP患者中,2例CML-CP患者停药后发生停药综合征,表现为全身骨骼或肌肉疼痛。结论接受长期TKI治疗、获得持续DMR的CML-CP患者,约50%在TKI停药后可获得长期TFR,但停药后仍需长期监测MR。上述可能影响TKI停药后临床结局的因素在分子学复发组和未复发组组间比较,差异均无统计学意义,这可能与本研究纳入样本量小相关。

To explore the clinical outcomes and their influencing factors of tyrosine kinase inhibitors (TKI) discontinuation in patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods From January 1999 to April 2018, a total of 16 patients with CML-CP who underwent routine outpatient follow-up in Department of Hematology, West China Hospital of Sichuan University, and discontinued TKI for more than 6 months were selected as subjects. Among them, there were 6 male patients and 10 females;the median age at diagnosis was 39.5 years (24.8-53.8 years). The median age at time of TKI discontinuation was 45.5 years old (30.3-69.0 years old). According to whether molecular recurrence occurred during the follow-up period after TKI discontinuation, the patients were divided into recurrent group (n=5) and non-recurrent group (n=11). The clinical data of patients with TKI before and after discontinuation were collected by retrospective method. The causes of TKI discontinuation, treatment-free remission (TFR) status after TKI discontinuation and its possible influencing factors were analyzed. In this study, composition ratio of gender, stage of CML, and TKI discontinuation causes were compared between the two groups using Fisher′s exact test. The Mann-Whitney U test was used to compare the non-normal distribution measurement data, such as duration of TKI treatment, time from TKI treatment to major molecular response (MMR)/deep molecular response (DMR), time of MMR/DMR maintenance. The TFR rate at 6 and 12 months after TKI discontinuation in patients was calculated by Kaplan-Meier method. The procedure followed in this study was in line with the revised Helsinki Declaration of the World Medical Association in 2013. Results ① Among all the 16 patients with CML-CP, causes of TKI discontinuation included TKI-related adverse reactions (n=5), patients′ expectancy (n=5), pregnancy/planned pregnancy (n=4), financial burden (n=1), and combined solid tumor (n=1). The median time of TKI treatment in 16 patients with CML-CP was 53.0 months (34.0-156.0 months). Among them, 15 patients achieved DMR before TKI discontinuation and 1 patient only obtained MMR. The median time to achieve DMR before TKI discontinuation was 39.0 months (10.0-144.0 months).② The median follow-up time of 16 patients with CML-CP after TKI discontinuation was 17.0 months (7.0-75.0 months). At the end of follow-up, 11 patients had no molecular recurrence, and the median time of TFR was 12.0 months (2.0-75.0 months). TFR rates at 6 and 12 months after TKI discontinuation were 68.8% and 61.9%, respectively. Molecular recurrence occurred in 5 patients. The median recurrence time was 4.0 months (2.0-5.0 months) after TKI discontinuation, and the BCR-ABLIS level was 0.14%-0.88% at the time of recurrence. Among the 5 patients with molecular recurrence, 4 patients restarted TKI at 3, 4, 6 and 8 months after relapse, obtained MMR after 2, 3, 4, and 5 months of restarting TKI, obtained molecular response (MR)^4.5 after 2, 3, 7 and 8 months of restarting TKI, respectively.③ In this study, 5 patients with molecular recurrence occurred within 6 months after TKI discontinuation. The composition ratio of gender, stage of CML, causes of TKI discontinuation, previous treatment of interferon-α, TKI type, as well as duration of TKI treatment, time of initiation of TKI treatment to MMR/DMR, time of MMR/DMR maintenance, age at TKI discontinuation between two groups were compared. And the differences were not statistically significant (P>0.05).④ Among 16 patients with CML-CP, 2 patients developed TKI withdrawal syndrome, which was characterized by systemic bone pain or myalgia. Conclusions Patients with CML-CP who receive long-term TKI and maintain continuous DMR, long-term TFR can be obtained in about 50% patients, but long-term MR should be monitored after TKI discontinuation. The above-mentioned influencing factors that may affect the clinical outcomes of TKI discontinuation were not statistically different between the recurrent group and the non-recurrent group, which may be related to small sample size of this study.